Postprandial proximal gastric acid pocket and its association with gastroesophageal acid reflux in patients with short-segment Barrett’s esophagus

Postprandial proximal gastric acid pocket and its association with gastroesophageal acid reflux in patients with short-segment Barrett’s esophagus 短节段Barrett’s食管的胃食管酸反流与餐后近端胃酸袋的相关性研究 1 first-author 1 corresp ‡Corresponding Authors ‡Corresponding Authors †E-mail:mxmxhk@163.comjun3z@163.com †E-mail:mxmxhk@163.comjun3z@163.com mxmxhk@163.com 2 2 2 1 2 corresp ‡Corresponding Authors ‡Corresponding Authors †E-mail:mxmxhk@163.comjun3z@163.com †E-mail:mxmxhk@163.comjun3z@163.com mxmxhk@163.com Department of Gastroenterology, the Second Affiliated Hospital of Baotou Medical College, Baotou 014040, China Department of Gastroenterology, the Second Affiliated Hospital of Baotou Medical College, Baotou 014040, China Department of Gastroenterology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710049, China Department of Gastroenterology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710049, China Objective: 2 To determine the characteristics of postprandial proximal gastric acid pockets (PPGAPs) and their association with gastroesophageal acid reflux in patients with Barrett’s esophagus (BE). Methods: 2 Fifteen patients with BE (defined by columnar lined esophagus of ≥1 cm) and 15 healthy individuals that were matched for age, gender, and body mass index, were recruited. The fasting intragastric pH and the appearance time, length, lowest pH, and mean pH of the PPGAP were determined using a single pH electrode pull-through experiment. For BE patients, a gastroesophageal reflux disease questionnaire (GerdQ) was completed and esophageal 24-h pH monitoring was carried out. Results: 2 The PPGAP was significantly longer (5 (3, 5) cm vs. 2 (1, 2) cm) and the lowest pH (1.1 (0.8, 1.5) vs. 1.6 (1.4, 1.9)) was significantly lower in patients with short-segment BE than in healthy individuals. The PPGAP started to appear proximally from the gastroesophageal pH step-up point to the esophageal lumen. The acidity of the PPGAP was higher in the distal segment than in the proximal segment. In short-segment BE patients, there were significant correlations between the acidity and the appearance time and length of the PPGAP. The length and acidity of the PPGAP were positively associated with gastroesophageal acid reflux episodes. The acidity of the PPGAP was associated with the DeMeester scores, the GerdQ scores, and the fasting intragastric pH. Conclusions: 2 In patients with short-segment BE, a PPGAP is commonly seen. Its length and acidity of PPGAP are associated with gastroesophageal acid reflux, the DeMeester score, and the GerdQ score in patients with short-segment BE. 目的 2 检测并分析短节段Barrett’s食管(BE)患者的餐后近端胃酸袋(PPGAP)的特点,并分析其与胃食管酸反流的相关性. 创新点 2 PPGAP可能是胃食管反流病的病理因素之一,引起广泛关注,而BE患者的PPGAP特点及与反流的相关性尚无报道. 方法 2 15名短节段BE患者和15名健康志愿者分别以牵拉法检测PPGAP的发生时间、长度、最低pH值和平均pH值.BE患者完成GerdQ问卷调查和24 h食管pH监测. 结论 2 短节段BE患者普遍存在PPGAP,同时PPGAP的长度和酸度与其胃食管酸反流周期数、DeMeester评分和GerdQ评分具有相关性. Short-segment Barrett’s esophagus Postprandial proximal gastric acid pocket (PPGAP) Gastroesophageal acid reflux 短节段Barrett’s食管 餐后近端胃酸袋(PPGAP) 胃食管酸反流 Introduction 1 Barrett’s esophagus (BE), defined by an extension of salmon-colored mucosa into the tubular esophagus ≥1 cm proximal to the gastroesophageal junction (Fitzgerald et al., 2014 2014 ; Falk, 2016 2016 ), is considered to be an adaptive change in the esophageal mucosa following prolonged exposure to an acidic environment (Kahrilas et al., 2013 2013 ). It has been demonstrated that BE is associated with a high risk of the development of esophageal and cardia cancers. Thus, extensive attention has been paid to the etiology, physiology, and pathogenesis of BE (Jankowski and Odze, 2009 2009 ). BE is a complication of chronic esophageal injury from gastroesophageal reflux disease (GERD), as a consequence of the replacement of reflux damaged esophageal squamous cells by mucous-secreting columnar cells. The length of BE with intestinal metaplasia positively correlates with the degree of acid reflux (Fitzgerald et al., 2014 2014 ). Therefore, BE originates from acid reflux. However, the role of acid reflux in the physiology of BE has not been fully elucidated. A postprandial proximal gastric acid pocket (PPGAP), defined by the presence of acidity (pH < 4) in a segment of the proximal stomach between distal (food) and proximal (lower esophageal sphincter or distal esophagus) nonacid segments, occurs in healthy individuals and patients with GERD (Fletcher et al., 2001 2001 ; Herbella et al., 2012 2012 ; Kahrilas et al., 2013 2013 ; Mitchell et al., 2016 2016 ). Previous studies have reported that patients with GERD have a higher incidence of PPGAPs with a longer length, a higher position, and a higher probability of acid reflux, than those observed in healthy individuals (Clarke et al., 2008 2008 ; Beaumont et al., 2010 2010 ; Kahrilas et al., 2013 2013 ). Recently, we published a study that analyzed the characteristics of PPGAPs in patients with GERD, which indicated that PPGAPs play an important role in GERD (Wu et al., 2018 2018 ). However, BE was not included in that study, and thus, the characteristics of PPGAPs in patients with BE remain unknown. PPGAP occurs in the part of the esophagus in which mucosal injury first appears and is most severe (Fletcher et al., 2004 2004 ). Considering this observation and the close association between PPGAP and GERD, we hypothesized that the occurrence of BE is due to constant acid exposure caused by a PPGAP in the gastroesophageal junction, and that PPGAPs play an important role in the physiology of BE. Therefore, the aim of the present study was to determine the characteristics of PPGAPs and the association between PPGAPs and gastroesophageal acid reflux in patients with BE. Materials and methods 1 Subjects 2 Patients aged ≥18 years, undergoing upper gastrointestinal endoscopy and diagnosed with BE according to the endoscopic appearance (i.e., columnar lined esophagus of ≥1 cm without histological evidence of intestinal metaplasia) between May 2014 and July 2015, were recruited for the study. According to the results of upper gastrointestinal endoscopy and upper abdominal ultrasound examination, patients with hiatus hernia, chronic atrophic gastritis, gastrointestinal tumors, peptic ulcer, diabetes mellitus, gallbladder diseases, or mental disorders, or those that had a history of surgery for upper gastrointestinal tract diseases, were excluded. In addition, healthy individuals matched for age, gender, and body mass index (BMI) were recruited from the community. GerdQ 2 At recruitment, all BE patients completed a GRED questionnaire (GerdQ), which is a questionnaire consisting of six parts providing an assessment of the degree of gastroesophageal reflux symptoms (Jones et al., 2009 2009 ). The GerdQ score is the sum of the scores from the six parts and ranges from 0 to 18. A patient was classed as GerdQ-positive if their GerdQ score was ≥8. Detection of PPGAPs 2 The method used for the detection of PPGAPs was similar to that described in our previous study (Wu et al., 2018 2018 ). Before examination, patients with BE and healthy individuals fasted for more than 8 h. Any drugs that might affect gastrointestinal motility or the pH of gastric juice were stopped for an individually determined amount of time: proton pump inhibitors (PPIs) were stopped for 7 d, H2 receptor blocking agents for 3 d, prokinetic agents for 2 d, and antacids for 6 h. An Omega dynamic impedance pH monitoring system (Medical Measurement Systems (MMS), the Netherlands) with a connected pH electrode, a portable recorder, and monitoring software was used. The pH electrode was calibrated with buffers of pH 4 and 7, separately, and distilled water was used to rinse the electrode before, or in between, immersion in a buffer. 2.3.1 Detection of pH changes in the distal esophagus and proximal stomach on fasting While the subject was in a seated position, the calibrated single channel pH electrode was pernasally inserted into the gastric cavity and the intragastric pH value was recorded. The electrode was then gradually withdrawn from the stomach to the esophagus. The gastroesophageal pH step-up point, the point at which the pH reading increased from the gastric pH level to the esophageal pH level (the pH step-up), was identified. The distance between the pH step-up point and the nasal tip was measured. Following this, the pH electrode was repositioned 5 cm below the pH step-up point, and pulled proximally at a rate of 1 cm/min, and the pH value at each detection point was recorded until the esophageal pH reading was observed. The electrode was then again positioned 5 cm beneath the pH step-up point. 2.3.2 Postprandial pH changes in the distal esophagus and proximal stomach Each individual subject was given 10–15 min to consume 150 g of bread, 30 g of ham sausage, and 100 mL of water. Ten minutes after consumption, the pH electrode was again pulled proximally at a rate of 1 cm/min. The pH value at each detection point was recorded until the esophageal pH was observed. The pH electrode was then once again repositioned 5 cm beneath the gastroesophageal pH step-up point. Postprandial pH changes at each detection point in the distal esophagus and proximal stomach were detected by repeated pull-through of the pH electrode. The distance from each detection point to the nasal tip was recorded with the time of detection and the pH value. The measurement was continued until the maximum range and peak acidity were detected. Then, the appearance of a PPGAP (i.e., when the pH value of the region between the distal esophagus and proximal stomach was ≥4 preprandially and <4 postprandially), and its appearance time (i.e., the period of time from the end of a standard meal to the time of PPGAP appearance), length (i.e., the length determined by the maximum acidified region during PPGAP appearance), lowest pH, and mean pH (i.e., the mean of the pH values detected at all the acidified points during PPGAP appearance) were calculated. Esophageal 24-h pH monitoring 2 For patients with BE, the pH electrode was placed 5 cm above the gastroesophageal pH step-up point after the detection of a PPGAP. Patients were then allowed to go home with a portable pH recorder. They were required to keep a record of meal time, postural changes, and gastroesophageal reflux symptoms, and were not allowed to have sweet, acidic, cold, or hot food, or carbonated beverages. After 24-h pH monitoring, the data were uploaded into the MMS system. Gastroesophageal acid reflux episodes and DeMeester scores were analyzed automatically. Pathological gastroesophageal acid reflux was defined by a DeMeester score of ≥14.72 in the esophageal 24-h pH monitoring. Statistical analysis 2 Data obtained from the present study are not normally distributed and thus are presented as the median and percentiles (first and third quartiles). Mann-Whitney U tests and Pearson’s correlation analysis were used to analyze data with a non-normal distribution, and Chi-square tests were performed to compare the categorical data between the two groups. The statistical analyses were performed using the statistical software SPSS 17.0 (Chicago, IL, USA). A P value of < 0.05 was considered to be statistically significant. Results 1 Comparison of PPGAPs between patients with BE and healthy individuals 2 Fifteen patients with short-segment BE with a length range of 1.0–3.0 cm (7 males and 8 females, ranging from 32–65 years of age) and 15 healthy individuals (7 males and 8 females, ranging from 31–66 years of age) were recruited. A PPGAP was detected in all subjects, but the PPGAP was significantly longer ( P =0.001) and the lowest pH was significantly lower ( P =0.013) in patients with short-segment BE than in the healthy individuals (Table 1 1 ). There was no significant difference in the mean pH of the PPGAP between the two groups, although the reading tended to be lower in patients with short-segment BE than in healthy individuals. Data are expressed as median (25th percentile, 75th percentile). P < 0.05. PPGAP: postprandial proximal gastric acid pocket; BE: Barrett’s esophagus  Group Time of PPGAP appearance (min) Length of PPGAP (cm) Lowest pH of PPGAP Mean pH of PPGAP  Patients with short-segment BE ( n =15) 14 (13, 19) 5 (3, 7) * * 1.1 (0.8, 1.5) * * 1.8 (1.6, 2.2)  Healthy individuals ( n =15) 19 (16, 21) 2 (1, 2) 1.6 (1.4, 1.9) 2.1 (1.7, 2.3) PPGAP in patients with BE 2 Observationally, the PPGAP started to appear proximally from the gastroesophageal pH step-up point to the esophageal lumen. The acidity of the PPGAP was higher in the distal than in the proximal segment. After the PPGAP was extended to the maximum length, its acidity continued to increase until a peak was reached. In patients with BE, there was no food buffering after meals within the 5-cm region beneath the gastroesophageal pH step-up point and the PPGAP: the acidity remained the same pre-and postprandially. The acidity in the esophagus above the PPGAP declined postprandially to a weak acid level (pH≥4). Fig. 1 1 shows the PPGAP profile of one patient with short-segment BE, as an example. In this patient, the pH values varied in the distal esophagus and the proximal stomach on fasting and postprandial duration. In this short-segment BE patient, the gastroesophageal pH step-up point was located 49 cm away from the nasal tip on fasting. The acidified part of the PPGAP was present at the start of the PPGAP detection cycle and extended proximally from the gastroesophageal pH step-up point, reaching its maximum range at 40 min and maximum acidity at 70 min after a meal. Correlations among the appearance time, length, and lowest pH of PPGAP in patients with BE 2 There was a significant correlation between the lowest pH and the appearance time ( r s =0.788, P < 0.001; Fig. 2a 2a ) and the length of the PPGAP in patients with short-segment BE ( r s =−0.915, P < 0.001; Fig. 2b 2b ). Correlation between PPGAP and gastroesophageal acid reflux in patients with BE 2 There were significant correlations between the length ( r s =0.969, P < 0.001; Fig. 3a 3a ) and acidity (i.e., lowest pH, r s =−0.876, P < 0.001; Fig. 3b 3b ) of the PPGAP and gastroesophageal acid reflux episodes. There were significant correlations between the acidity (i.e., mean pH) of the PPGAP and the GerdQ ( r s =−0.854, P < 0.001; Fig. 4a 4a ) and the DeMeester scores ( r s =−0.914, P =0.007; Fig. 4b 4b ) in patients with BE. The lowest pH of the PPGAP was significantly associated with the fasting intragastric pH in patients with BE ( r s =0.765, P =0.001; Fig. 5 5 ). Discussion 1 In this study, a PPGAP was present in all healthy individuals and patients with short-segment BE. The PPGAP was significantly longer and its pH was significantly lower in patients with short-segment BE than in healthy individuals. Furthermore, in patients with short-segment BE, the lowest pH of the PPGAP was associated with its appearance time and length. The length and pH of the PPGAP were significantly correlated with gastroesophageal acid reflux episodes, and the pH of the PPGAP was associated with the DeMeester scores, GerdQ scores, and the fasting intragastric pH. These findings indicate that PPGAPs may play important roles in the pathology of short-segment BE, although further investigation with a larger number of patients is required to draw a firm conclusion. A PPGAP has been reported to appear 10–15 min after a meal in patients with GERD and 19 min after a meal in healthy individuals (Clarke et al., 2008 2008 ; Beaumont et al., 2010 2010 ; Wu et al., 2018 2018 ). In our study, PPGAPs were detected in patients with short-segment BE 10 min after a standard meal, and the median appearance time was 14 min. The acidified part of the PPGAP was already present at the start of PPGAP detection in some patients, suggesting that it may have appeared just a few minutes after the standard meal. In healthy individuals, PPGAPs occurred 19 min after a meal. This suggests that PPGAP detection should be started immediately following a standard meal in patients with short-segment BE. In this study, PPGAPs extended proximally from the gastroesophageal pH step-up point, and a higher level of acidity (lower pH) was generally found in the distal segment of the PPGAP both in patients with short-segment BE and in healthy individuals. After the PPGAP had extended to its maximum range, its acidity continued to increase until a peak was reached. The PPGAP then gradually reduced from the proximal segment with a decline in both its length and acidity. A decline in the esophageal pH was also detected above the PPGAP with a weak acidity (high pH). This process of change in the PPGAP has not been reported before. Reflux episodes are conventionally measured 5 cm proximal to the proximal margin of the lower esophageal sphincter. However, mucosal pathology is usually limited to the distal esophageal mucosa, which is consistent with the location of BE (Grigolon et al., 2009 2009 ). Fletcher et al. ( 2004 2004 ) found that 24-h esophageal acid exposure was about six times greater at 0.5 cm than at 5.5 cm proximal to the squamocolumnar junction, and acid exposure adjacent to the squamocolumnar junction is less likely to be symptomatic than conventionally measured reflux. Long-term exposure to acid and weak acidity (high pH) due to a PPGAP may contribute to mucosal inflammation, intestinal metaplasia, and BE. This phenomenon is pathophysiologically important, especially for patients with short-segment BE or BE without reflux symptoms. It remains unclear how PPGAPs develop in patients with short-segment BE. Previous studies have reported that several factors, such as the escape of gastric juice from neutralization by food in the proximal stomach, gastric motility, gastric anatomical structure, hiatus hernia, and types of food, may be involved in the formation of the acid pockets (Hila et al., 2006 2006 ; McColl et al., 2010 2010 ; Boecxstaens et al., 2011 2011 ; Curcic et al., 2012 2012 ; Herbella et al., 2012 2012 ). The persistence of acid in the proximal stomach would be facilitated by the relative quiescence of the most proximal part of the stomach after a meal, with motor contractions arising distal to this point and then moving toward the antrum (Fletcher et al., 2001 2001 ). Hiatus hernia impairs gastroesophageal motility by lowering both the esophageal sphincter function and esophageal clearance. Thus, the presence of hiatus hernia may influence the size and position of a PPGAP (McColl et al., 2010 2010 ). Conversely, other study has indicated that PPGAPs may result from postprandial gastroesophageal acid reflux (Rohof et al., 2014 2014 ). To rule out the confounding influence of hiatus hernia on the association between BE and PPGAPs, we excluded patients with hiatus hernia from the present study. The acid pockets in the patients studied were remarkably long. This may be because although hiatal hernia is associated with acid pockets, other factors as mentioned above may contribute to long acid pockets. In the present study, no postprandial food buffering was found within the region 5 cm beneath the gastroesophageal pH step-up point in patients with short-segment BE, although all patients had a PPGAP. This suggests that postprandial food buffering or neutralization is not an essential factor for the formation of a PPGAP in patients with short-segment BE. However, the theory that PPGAPs can be caused by escape from neutralization by food needs to be verified in further studies. The present study showed that a low gastric pH under fasting correlated with a low pH of PPGAPs in patients with short-segment BE, which partly explained the therapeutic effect of PPIs and other drugs on PPGAPs (Sweis et al., 2013 2013 ; Rohof et al., 2014 2014 ). A recent study reported that patients with Helicobacter pylori infection had a reduced range and intensity of PPGAP, which was considered to be associated with the decreased acidity (increased pH) caused by the infection (Mitchell et al., 2017 2017 ). Herbella et al. ( 2010 2010 , 2011a 2011a , 2011b 2011b ) showed that PPGAPs were uncommon after Nissen fundoplication, distal gastrectomy, and Roux-en-Y gastric bypass (RYGB). This can be explained by the small size of the gastric pouch and the lack of stimulus to the antrum after surgery, resulting in a reduction or absence of acid production in the stomach. Therefore, we assume that, in patients with short-segment BE, the level of gastric acid may directly affect the development and severity of PPGAPs. The present study revealed positive correlations between the acidity, length of PPGAPs and the gastroesophageal acid reflux, DeMeester score, GerdQ score in patients with short-segment BE. It is accepted that DeMeester scores are an objective indicator of the severity of gastroesophageal acid reflux and that GerdQ scores are correlated with the degree of subjective symptoms of gastroesophageal reflux. Therefore, consistent with our previous observation (Wu et al., 2018 2018 ), the findings of this study indicate that PPGAPs play an important role in esophageal acid reflux and gastroesophageal symptoms in short-segment BE. There were several limitations in the present study. First, the number of subjects, including those with short-segment BE and the healthy individuals, was relatively small. This was mainly because the procedure of PPGAP detection is complicated and time-consuming (duration: 3–4 h). For PPGAP detection, multiple pull-throughs (5–7) are required for each subject, which is associated with poor tolerance. Therefore, it is difficult to recruit subjects, especially healthy individuals who are age-, gender-and BMI-matched to the patients with BE. Second, patients with long-segment BE were not included in this study. This was because we encountered very few patients with long-segment BE. Thus, the findings in the present study may reflect the characteristics of PPGAP only in patients with short-segment BE, and further investigation with long-segment BE patients is required in future studies. Third, the total duration of each PPGAP was not determined in the present study. Previous studies have indicated that this parameter was 90–120 min (Simonian et al., 2005 2005 ; Clarke et al., 2009 2009 ; Wu et al., 2018 2018 ). 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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. 10.1631/jzus.B1900498 Project supported by the Natural Science Foundation of Inner Mongolia Autonomous Region (Nos. 2019LH08042 and 2018MS08050) and the Natural Science Foundation of Baotou Medical College (No. BYJJ-YF-2018024), China 2019-08-16 2019-12-15 2022-01-05 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2020 2020 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 07 21